The skin is the largest organ of the body and protects mammalian organisms from both aqueous and xerotic ambient environments. The maintenance of a barrier against excessive transcutaneous water loss to the environment is critical to survival of all terrestrial animals. In mammals, this barrier is formed by the anucleate, cornified, outermost layers of the epidermis, collectively known as the stratum corneum. Both the surfaces of mucous membranes and the deepest layers of the stratum corneum contain high concentrations of glycosphingolipids which are metabolized progressively to ceramides as the stratum granulosum becomes anucleate with outward maturation. Localized or generalized perturbations of the epidermal barrier occur in a variety of diseases and conditions of the skin and mucous membrane. These perturbations not only contribute significantly to the morphology of the cutaneous lesions, but also activate certain skin diseases, for example the Koebner phenomenon in psoriasis. Common moisturizers and emollients also cause disruptions of the barrier function.
It is now generally accepted that the intercellular, lamellar bilayer sheets of stratum corneum lipids are the key constituents for a functional barrier. The epidermal lipids consist of a mixture of polar and nonpolar species. The three dominant lipids by weight are ceramides (40%), cholesterol (20-25%) and free fatty acids (20-25%). The latter group include the essential fatty acid, linoleic acid, as well as additional nonessential fatty acids. The human epidermis further contains a unique acylsphingolipid whose molecular structure includes a sphingoid backbone with a 30-carbon, .alpha.-hydroxy acid residue joined to the backbone through an amide linkage, the residue itself being .omega.-esterified with linoleic acid.
Although each of the lipid species is important for stratum corneum homeostasis, ceramides are of particular importance because of their large weight contribution and structural characteristics. The moisturization properties of ceramides are known. A published Japanese patent application of Kao Company Limited (No. 24391-1987) discloses a formulation containing bovine ceramide with a sphingoid base of 10 to 26 carbon atom length and one or more of any of the other stratum corneum lipids. The purpose of this formulation is to increase water retention and improve skin roughness (moisturization).
Despite the potential efficacy of lipids as moisturizer ingredients, studies have demonstrated that many of the individual lipids, including ceramides and lipid combinations which are disclosed in the Kao disclosure for their moisturization properties, actually impede rather than facilitate barrier repair when applied to damaged skin. Formulations of this kind will therefore worsen the lesions of skin and mucous membrane diseases because an acute or chronically damaged epidermal barrier responds differently than either normal skin or merely dry, rough skin when epidermal lipids are applied.
While substances which effect barrier repair are all effective as moisturizers as well, the converse is not true. For example, scaling and roughness of the skin are a manifestation of an abnormally desquamating stratum corneum, but often these conditions do not correlate with the function of the stratum corneum barrier. Patients suffering from atopic dermatitis, for example, have skin with an incompetent barrier, as measured by trans-epidermal water loss, but no visible scaling.
Moisturizers are defined as substances which increase the stratum corneum water content. Skin conductance measurements are the most accurate assay of the water content. High skin conductance measurements indicate high water content. While high water content indicates a high degree of moisturization, it is not an indication of good barrier function. Mucous membranes, for example, are moist with an extremely high water content but poor barrier function. Nor does the thickness of the stratum corneum correlate with barrier function. Palms and soles which appear normal have the thickest stratum corneum and a high water content but relatively poor barrier function.
While all moisturizers will temporarily decrease visible scaling and roughness, they usually offer little or no improvement to the integrity of the stratum corneum barrier.
The importance of the three major epidermal lipids to the integrity of the epidermal barrier is demonstrated by their increased synthesis after both acute and chronic barrier disruption. Inhibition of their respective rate-limiting enzymes causes a reduction in concentration of any one of these three major epidermal lipids and thereby produces significant delay in the recovery of barrier function.
Lovastatin, an inhibitor of cholesterol synthesis, produces a barrier defect when applied to normal epidermis. After lovastatin is applied, cholesterol synthesis rapidly normalizes, but fatty acid synthesis remains elevated. This suggests that a disturbance in the fatty acid:cholesterol ratio accounts for the perturbed barrier function.
Although logic would suggest that application of each of the lipids individually or with another lipid in a two-component system should accelerate barrier recovery when applied to damaged skin, this does not in fact occur. For example, in mice which suffer a barrier defect due to a deficiency in the essential fatty acid, linoleic acid, topical application of linoleic acid alone further aggravates barrier dysfunction until the systemic deficiency state is corrected.
The following are situations and cutaneous conditions which involve or give rise to a disrupted or dysfunctional epidermal barrier:
1) Important causes of morbidity and mortality in premature infants less than 33 weeks of gestational age are fluid and electrolyte abnormalities, hypothermia, and infection with the skin being the portal of entry. The development of mature barrier function coincides with the deposition of adequate amounts of the three major epidermal lipids in appropriate proportions. PA1 2) Eczematous dermatitides are a group of inflammatory hyperproliferative skin diseases characterized by poorly demarcated, scaly, itchy or tender patches that may involve wide-spread areas of the body. Two of the most common types are atopic and seborrheic dermatitis. Both have a genetic predisposition and display abnormalities of stratum corneum lipids and barrier function even in clinically uninvolved skin. The other major eczematous dermatitides result from environmental or occupational insults of solvents, chemicals, detergents, hot water, low ambient humidity, ultraviolet or X radiation. These disorders include allergic or irritant contact dermatitis, eczema craquelee, photoallergic, phototoxic, or phytophotodermatitis, radiation, and stasis dermatitis. Eczema craquelee begins as dehydrated or dry skin that reaches such severity that complete destruction of the epidermal barrier occurs, which results in inflammation and hyperproliferation. The predominant therapy for eczematous dermatitides comprises topical corticosteroids and systemic antihistamines with or without antibiotics. Unfortunately, the skin remains excessively sensitive for months after the apparent clinical resolution of the lesions which results in rapid rebound of the lesions with significantly less environmental insult. Therefore, there is a great need for an effective therapeutic formulation that will normalize the barrier of both clinically uninvolved and involved skin to prevent disease exacerbations and/or limit disease extent. PA1 3) Ulcers and erosions result from trauma or ischemia of the skin or mucous membranes. These insults include chemical or thermal burns, and vascular compromise as in venous, arterial, embolic or diabetic ulcers. The lesions are not only painful but form a portal for pathogenic microbes. Current therapy consists primarily of antibiotics, occlusive dressings, and vascular compression bandages. PA1 4) The ichthyoses are a group of incurable, disfiguring common to rare genetic diseases characterized by disorders of abnormal epidermal cornification with or without associated abnormal barrier function and epidermal hyperproliferation. The palliative treatments for these diseases consist of systemic and topical retinoids, and topical .alpha.-hydroxy and salicylic acids. These modalities can produce significant topical irritation and both systemic retinoids and topical salicylic acid carry a significant risk of serious systemic toxicity. PA1 5) The epidermolysis bullosae are a group of rare genetic diseases resulting from an absence or defect in epidermal/dermal cohesion. Cutaneous trauma to normal skin with normal daily activity results in complete or partial loss of the epidermis producing blisters, erosions, and ulcers. The only therapy for one type is diphenylhydantoin and/or systemic retinoids. Both treatments produce a significant number of severe systemic side effects with chronic usage. PA1 6) Psoriasis is a markedly hyperproliferative, inflammatory papulosquamous disease characterized by sharply demarcated, scaly plaques most frequently located at areas of the body which suffer trauma, specifically knees, elbows, hands, feet, and scalp. Nearly all of the currently available topical and systemic therapies carry a significant risk of systemic and/or cutaneous toxicity. Moreover, these treatments generally are followed by a rapid rebound of the disease when they are withdrawn. None of these treatments repair the barrier and some actually worsen it. The current medications include: retinoids, corticosteroids, sulfones, antineoplastic agents, anthralin, tar, psoralens and ultraviolet A or B light. It has recently been reported that prolonged remission was achieved in 60% of lesions treated with weekly applications of occlusive tape for a 10-week period. This modality artificially restores epidermal barrier function to some degree. PA1 7) The cutaneous changes of intrinsic aging and photoaging (dermatoheliosis) result from environmental ravages combined with intrinsic changes which produce atrophy, fragility, inelasticity, decreased cell cohesion, hypoproliferation, and delayed healing after insults to the barrier. The stratum corneum lipids display a depletion of ceramide and nonpolar lipid species with a relative increase in cholesterol. The current treatments consist of topical application of retinoids or .alpha.-hydroxy acids, both of which often produce irritation, especially in the elderly. PA1 8) The limiting factor for occupational or athletic performance, even for the occasional recreational athlete is frictional blistering of the skin by mechanical shearing forces. Prevention with layered clothing or application of synthetic films are the only currently available, somewhat helpful remedies. PA1 9) The major limiting factor for the topical use of corticosteroids, especially in the young and elderly is cutaneous atrophy which predisposes to infection and slows the rate of healing. Topical retinoids and .alpha.-hydroxy acids may partially reverse the atrophy, but the irritation potential of these agents is significantly increased. PA1 10) There are many known or potential therapeutic compounds whose utility has been prevented or is compromised because of cutaneous irritation or barrier disruption. A formulation comprising these compounds incorporated with the lipids of this invention will expand the therapeutic armamentarium potentially available to physicians.
The integrity of the epidermal barrier is known to be the major factor that regulates epidermal DNA synthesis. It is also known that maintenance of a normal epidermal barrier will inhibit epidermal hyperproliferation. The discoveries of the present invention, therefore, lead to treatments for hyperproliferative cutaneous diseases, notable examples of which are papulosquamous and eczematous diseases.